Annexin 2, also known as annexin A2, annexin II, lipocortin II, galpactin I heavy chain, chromobindin-8, p36 or placental anticoagulant protein IV, is a 38 kDa protein which is part of the annexin family. Annexins are proteins which have a dual cell location: cytosolic and membrane. It is encoded in humans by the ANXA2 gene. Annexin 2 is structured as 2 domains: the core which contains the Ca2+-binding sites responsible for binding to membranes, and the N-terminal domain which has the site for binding to the S100A10 protein with which it forms a tetramer.
Annexin 2 is involved in numerous functions: angiogenesis, the metastatic process, cholesterol transport, infection by certain viruses, exocytosis and endocytosis phenomena, regulation of the action of plasminogen, fibrinolysis, ion channel formation, membrane-cytoskeleton interactions, intercellular junction formation (for a review, see Hajjar, K. A. & S. Krishnan (1999) Trends in Cardiovascular Medicine 9(5): 128-138).
From a pathological point of view, the overexpression of annexin A2 has been found in several human cancers, including, but not restricted to, high-grade glioma, acute promyelocytic leukemia, colorectal cancer, pancreatic cancer, renal deli carcinomas, hepatocellular carcinomas, squamous cell carcinomas, prostate cancer and lung cancer. The overexpression of annexin 2 has, moreover, been correlated with poor prognosis in colorectal cancer (Emoto et al. (2001). Cancer 92: 1419-26) and with a risk of recurrence after surgery in patients suffering from pancreatic cancer (Takano et al. (2008). Ann Surg Oncol 15:3157-68).
The involvement of annexin 2 has been reported in several diseases. Thus, it appears that abnormally high levels of annexin 2 expression on acute promyelocytic leukemia cells increase the production of plasmin, which is a fibrinolytic protein, thereby contributing to the hemorrhagic complications observed in this leukemia (Menell et al. (1.999) New England Journal of Medicine 340: 994-1004; Hajjar & Krishnan (1999) Trends Cardiovasc. Med. 9: 128-138 Stein et al. (2009) Best Pract. Res. Clin. Haematol. 22: 153-63).
It has also been reported that annexin 2 appears to promote angiogenesis, tumor progression and also metastases of certain cancers (Yusuke, S. et al. (2008) Journal of Cellular Biochemistry 105(2): 370-380).
Moreover, annexin 2 also appears to be involved in the increased risk of arterial and venous thrombosis run by patients bearing antiphospholipid antibodies (APLAs) (Zhang & McCrae (2005) Blood 105: 1964-1969). Annexin 2 also appears to promote the infection of cells by certain viruses.
Annexin 2 is therefore a promising therapeutic target and also an interesting diagnostic marker, and is would be advantageous to have ligands specific for this protein, whether in order to block its pathological functions or to detect it.
In this respect, it has been shown that several, protein ligands of annexin 2 have a therapeutic action. Thus, it has been shown in mice that a monoclonal antibody directed against annexin 2 makes it possible to reduce tumor growth by 70% in a murine model of Lewis lung carcinoma. (Sharma et al. (2006) Exp. Mol. Pathol. 81: 136-145). Similarly, it has been demonstrated that the anti-angiogenic effect of the TM601 polypeptide, a synthetic form of chlorotoxin, appears to be linked to its interaction with annexin 2 (Kesavan et al. (2010) J. Biol. Chem. 285: 4366-4374; Lima et al. (2010). J Cell Physiol 225: 855-864). Moreover, it has been shown that the Fab fragment of an anti-annexin 2 monoclonal antibody blocks the endothelial activation caused by APLAs (Zhang & McCrae (2005) Blood 105: 1964-1969).
However, the annexin 2 ligands identified to date have limitations, in particular in terms of synthesis cost, immunogenicity or affinity for their target.